Multi-well rotary synthesizer

ABSTRACT

An apparatus for synthesizing polymer chains includes a controller, a plurality of precision fit vials circularly arranged in multiple banks on a cartridge, a drain corresponding to each bank of vials, a chamber bowl, a plurality of valves for delivering reagents to selective vials, and a waste tube system for purging material from the vials. A purging operation can be selectively performed on one or more of the banks of vials. The multiple banks of valves provide an additional number of reagent choices while operating in a serial mode and faster reagent distribution while operating in a parallel mode. The plurality of vials are stored in the cartridge and are divided among individual banks wherein each bank of vials has a corresponding drain. There is at least one waste tube system for expelling the reagent solution from vials within a particular bank of vials when the waste tube system is coupled to the corresponding drain. The cartridge holding the plurality of vials rotates relative to the stationary banks of valves and the waste tube system. The controller rotates the cartridge and operates the banks of valves and the waste tube system in response to the required sequence of dispensing various reagent solutions and flushing appropriate vials in order to form the desired polymer chain within each vial.

RELATED APPLICATIONS

This is a continuation of U.S. patent application Ser. No. 09/742,803,filed Dec. 19, 2000, and entitled MULTI-WELL ROTARY SYNTHESIZER which isa divisional of U.S. patent application Ser. No. 09/097,966, filed Jun.16, 1998, now issued as U.S. Pat. No. 6,270,730, the contents of whichare both hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to the field of synthesizers. Moreparticularly, this invention relates to synthesizers that utilizemultiple banks of vials to synthesize custom sequence definedoligonucleotides, polymers, and other organic compounds.

BACKGROUND OF THE INVENTION

Oligonucleotides are playing an increasingly important role indiagnostic medicine, forensic medicine, and molecular biology research.In addition to oligonucleotides, polymers such as peptides,polynucleotides, and other organic chains are also very important inscientific research.

Accordingly, the use of and demand for synthetic oligonucleotides,polymers, and organic chains has increased. In turn, this has spawneddevelopment of new synthesis systems and methods for basic proceduresfor custom sequence defined oligonucleotides, polymers, and otherorganic chains.

Typically, the present automated systems and methods place a solidsupport such as controlled pore glass beads (CPG) into a plurality ofindividual vials which provide a stable anchor to initiate the synthesisprocess. Using a series of valves, the selected reagents aresequentially placed into the appropriate vial in a predeterminedsequence. Contact of the reagent with the CPG inside each of the vialscauses a reaction that results in sequenced growth thereon. Sequentialdeposits of the selected reagents within the vials build thepredetermined sequence.

A flushing procedure is typically utilized after a particular reagent isplaced into one of the vials for a predetermined amount of time. Whilethe particular reagent contacts the CPG a reaction produces a sequencedgrowth on the CPG. In conventional synthesis machines the flushingprocedure is performed on all the vials simultaneously. During aflushing operation within conventional synthesis machines, all thereagents within the plurality of individual vials are flushed andexpelled through a shared central orifice within the synthesis machine.After completion of a flushing operation, the plurality of vials arethen capable of receiving another reagent.

In High Throughput DNA Synthesis in a MultiChannel Format, L. E.Sindelar and J. M. Jaklevic teach an approach to high throughputparallel DNA synthesis in which a multi-vial format is utilized. Thereactions are carried out in open vials. Each vial contains CPG to formthe substrate for the synthesis and a high density filter bottom toretain the CPG within each vial. There is a common vacuum line that iscoupled to all the vials. This common vacuum line simultaneously flushesthe material contained within all the vials. The synthesis of a DNAsequence is carried out by directly dispensing reagents into individualreaction vials. A computer controls the sequence in which reagents aredispensed and timing periodic flushing operations to expel material fromthe reaction vials.

U.S. Pat. No. 5,529,756, by Brennan, teaches an apparatus and method forpolymer synthesis utilizing arrays. This apparatus includes an array ofnozzles with each nozzle coupled to a reservoir containing a reagent anda base assembly having an array of reaction vials. A transport mechanismaligns the reaction vials and selected nozzles to deposit an appropriatereagent to a selected vial. Each of the reaction vials has an inlet forreceiving a reagent and an outlet for expelling a material. To perform aflushing operation, this apparatus creates a pressure differentialbetween the inlet and outlet of the array of vials. During the flushingoperation, material within each of the array of vials are simultaneouslyexpelled.

A retaining device is customarily utilized to ensure that the CPGremains within the corresponding vial during the flushing procedure.This retaining device is located within each individual vial and ispositioned to prevent the CPG from exiting the orifice during theflushing procedure.

Conventional automated synthesis systems perform the flushing operationsimultaneously on all vials within the system. Conventional automatedsynthesis systems lack the ability to selectively perform the flushingoperation on groups of vials within the system.

What is needed is a synthesizer that is configured to selectivelyperform depositing and flushing operations on groups of vials within thesystem.

SUMMARY OF THE INVENTION

A multi-well rotary synthesizer includes a controller, a plurality ofprecision fit vials circularly arranged in multiple banks on acartridge, a drain corresponding to each bank of vials, a chamber bowl,a plurality of valves for delivering reagents to selective vials, and awaste tube system for purging material from the vials. The banks ofvials can be selectively purged, allowing the banks of vials to be usedto synthesize different polymer chains. Further, the multiple banks ofvalves provide an additional number of reagent choices while operatingin a serial mode and faster reagent distribution while operating in aparallel mode.

The plurality of vials are held within the cartridge and are dividedamong individual banks. Preferably, each individual bank of vials has acorresponding drain. There is at least one waste tube system forexpelling the reagent solution from vials within a particular bank ofvials when the waste tube system is coupled to the corresponding drain.The cartridge holding the plurality of vials rotates relative to thestationary banks of valves and the waste tube system. The controllercontrols a motor to rotate the cartridge. The controller also operatesthe banks of valves and the waste tube system in response to therequired sequence of dispensing various reagent solutions and flushingappropriate vials in order to create the desired polymer chain.

A frit is inserted into each vial and serves as a filter and to hold theCPG within the vial. The interior of each vial is precision bored toensure a tight consistent seal with the corresponding frit. Thisconsistent seal with the frit for every vial also results in aconsistent reagent solution flow through every vial. The exterior ofeach vial also has a precise dimension to consistently fit within thecartridge and provide a pressure tight seal around each vial within thecartridge.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a perspective view of the synthesizer of the presentinvention.

FIG. 2 illustrates the preferred cartridge of the present invention.

FIG. 3 illustrates a perspective view of an alternate cartridge.

FIG. 4 illustrates a cross-sectional view of the synthesizer of thepresent invention.

FIG. 5 illustrates a top view of the drain plate.

FIG. 6 illustrates a cross-sectional view of the vial.

FIG. 7 illustrates a cross-sectional view of the waste tube system.

FIG. 8 illustrates the controlling computer coupled to the synthesizerof the preferred embodiment of the present invention.

FIG. 9 illustrates a cross-sectional view of an alternate waste tubesystem.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

While the present invention will be described with reference to severalspecific embodiments, the description is illustrative of the presentinvention and is not to be construed as limiting the invention. Variousmodifications to the present invention can be made without departingfrom the scope and spirit of the present invention. For the sake ofclarity and a better understanding of the present invention, commoncomponents share common reference numerals throughout various figures.

FIG. 1 illustrates a synthesizer 100. The synthesizer 100 is designedfor building a polymer chain by sequentially adding polymer units to asolid support in a reagent solution. The solid support generally resideswithin a vial and various reagent solutions are sequentially added tothe vial. Before an additional reagent solution is added to the vial,the previous reagent solution is preferably purged from the vial.Although, the synthesizer 100 is particularly suited for buildingsequence defined oligonucleotides, the synthesizer 100 is alsoconfigured to build any other desired polymer chain or organic compound.The term “polymer chain” is defined as a unit that is bound to otherunits of the same or different kind to form a polymer chain, such asoligonucleotides and peptide chains. It is important to note thatalthough the present invention is described in context of specificapplications, the present invention should not be limited to thesespecific examples disclosed herein.

The synthesizer 100 preferably comprises at least a bank of valves andat least one bank of vials. Within each bank of vials, there is at leastone vial for holding the solid support and for containing a reagentsolution such that a polymer chain can be synthesized. Within the bankof valves, there are preferably a plurality of valves configured forselectively dispensing a reagent solution into one of the vials. Thesynthesizer 100 is preferably configured to allow each bank of vials tobe selectively purged of the presently held reagent solution. Additionalbanks of valves provide the synthesizer 100 with greater flexibility.For example, each bank of valves can be configured to distribute reagentsolutions to a particular bank of vials in a parallel fashion tominimize the processing time. Alternatively, multiple banks of valvescan be configured to distribute reagent solutions to a particular bankof vials in series thus allowing the synthesizer 100 to hold a largernumber of different reagent solutions, thus being able to create complexpolymer chains.

FIG. 1 illustrates an exterior perspective view of a rotary synthesizer100. As illustrated in FIG. 1, the synthesizer 100 includes a base 105,a cartridge 170, a first bank of vials 115, a second bank of vials 125,a plurality of dispense lines 140, a plurality of fittings 150, a firstbank of valves 110 and a second bank of valves 120. Within each of thebanks of valves 110 and 120, there is preferably at least one valve.Within each of the banks of vials 115 and 125, there is preferably atleast one vial. Each of the valves is capable of selectively dispensinga reagent solution into one of the vials. As stated before, each of thevials is preferably configured for retaining a solid support such as CPGand holding a reagent solution. Further, as each reagent solution issequentially deposited within the vial and sequentially purgedtherefrom, a polymer chain is generated.

Preferably, there is a plurality of reservoirs (not shown) eachcontaining a specific reagent solution to be dispensed to one of theplurality of valves 130. Each of the valves within the first bank andsecond bank of valves 110 and 120, is coupled to a correspondingreservoir. Each of the plurality of reservoirs is pressurized. As aresult, as each valve is opened, a particular reagent solution from thecorresponding reservoir is dispensed to a corresponding vial.

Each of the plurality of dispense lines 140 is coupled to acorresponding one of the valves within the first and second banks ofvalves 110 and 120. Each of the plurality of dispense lines 140 providesa conduit for transferring a reagent solution from the valve to acorresponding vial. Each one of the plurality of dispense lines 140 ispreferably configured to be flexible and semi-resilient in nature.Preferably, the plurality of dispense lines 140 are each coated withTeflon® which is more resistant to deterioration upon contact withreagent solutions and provides an adequate seal between the plurality ofvalves 130 and the plurality of fittings 150. Further, each of theplurality of fittings 150 is preferably coupled to one of the pluralityof dispense lines 140. The plurality of fittings 150 are preferablyconfigured to prevent the reagent solution from splashing outside thevial as the reagent solution is dispensed from a cap to a particularvial positioned below the cap.

As shown in FIG. 1, the first and second banks of valves 110 and 120each have thirteen valves. In FIG. 1, the number of valves in each bankis merely for exemplary purposes. It is preferable to have fifteenvalves for each bank even though the illustrated cartridge 170 only hastwelve vials per bank. The present invention provides greaterflexibility in creating complex polymer chains by including a greaternumber of valves than vials per bank. It should be apparent to thoseskilled in the art that any appropriate number of valves can be includedwithin each bank of valves.

Each of the vials within the first bank of vials 115 and the second bankof vials 125 is presently shown resting in one of a plurality ofreceiving holes 185 within the cartridge 170. Preferably, each of thevials within the corresponding plurality of receiving holes 185 ispositioned in a substantially vertical orientation. Each of the vials isconfigured to retain a solid support such as CPG and hold a reagentsolution. Preferably CPG is utilized as this solid support.Alternatively, any other appropriate solid support can be used tosupport the polymer chain being synthesized.

In use, each of the valves selectively dispenses a reagent solutionthrough one of the plurality of dispense lines 140 and fittings 150. Thefirst and second banks of valves 110 and 120 are preferably coupled tothe base 105 of the synthesizer 100. The cartridge 170 which containsthe plurality of vials 181 rotates relative to the synthesizer 100 andrelative to the first and second banks of valves 110 and 120. Byrotating the cartridge 170, a particular vial 181 can be positionedunder a specific valve such that the corresponding reagent solution fromthis specific valve is dispensed into this vial. Further, the first andsecond banks of valves 110 and 120 are capable of simultaneously andindependently dispensing reagent solutions into corresponding vials.

FIG. 2 illustrates a detailed view of the cartridge 170. Preferably, thecartridge 170 is circular in shape such that the cartridge 170 iscapable of rotating in a circular path relative to the base 105 and thefirst and second banks of valves 110 and 120. The cartridge 170 has aplurality of receiving holes 185 on its upper surface around theperipheral edge of the cartridge 170. Each of the plurality of receivingholes 185 is configured to hold one of the vials 181 within the firstbank of vials 115 and the second bank of vials 125. The plurality ofreceiving holes 185 as shown on the cartridge 170 are divided up amongfour banks. A bank 180 illustrates one of the four banks on thecartridge 170 and contains twelve receiving holes wherein each receivinghole is configured to hold a vial. An exemplary vial 181 is shown beinginserted into one of the plurality of receiving holes 185. The totalnumber of receiving holes shown on the cartridge 170 includesforty-eight (48) receiving holes divided into four banks of twelvereceiving holes each. The number of receiving holes and theconfiguration of the banks of receiving holes is shown on the cartridge170 for exemplary purposes only. It should be apparent to those skilledin the art that any appropriate number of receiving holes and banks ofreceiving holes can be included in the cartridge 170. Preferably, thereceiving holes 185 within the cartridge each have a precise diameterfor accepting the vials 181, which also each have a correspondingprecise exterior dimension to provide a pressure-tight seal when thevials 181 are inserted into the receiving holes 185.

FIG. 3 illustrates an alternative cartridge 300. The cartridge 300 issimilar to the cartridge 170 shown in FIGS. 1 and 2. Each of thereceiving holes 320 is configured to hold a vial 181. A plurality ofreceiving holes are grouped together to form a bank of receiving holes310. The cartridge 300 contains a total of ninety-six (96) receivingholes grouped into twelve banks, each bank including eight receivingholes. The number of receiving holes and the configuration of the banksof receiving holes included on the cartridge 300 is exemplary only.

FIG. 4 illustrates a cross sectional view of the synthesizer 100. Asillustrated in FIG. 4, the synthesizer 100 includes the base 105, a setof valves 470, a motor 445, a gear box 440, a chamber bowl 400, a drainplate 410, a drain 740, the cartridge 170, a chamber seal 450, a motorconnector 465, a waste tube system 430, a controller 480, and a clearwindow 460. The valves 470 are coupled to the base 105 of thesynthesizer 100 and are preferably positioned above the cartridge 170around the outside edge of the base 105. This set of valves 470preferably contains fifteen individual valves which each deliver acorresponding reagent solution in a specified quantity to a vial held inthe cartridge 170 positioned below the valve. Each of the valves maydispense the same or different reagent solutions depending on theuser-selected configuration. When more than one valve dispenses the samereagent solution, the set of valves 470 is capable of simultaneouslydispensing a reagent solution to multiple vials within the cartridge170. When the valves 470 each contain different reagent solutions, eachone of the valves 470 is capable of dispensing a corresponding reagentsolution to any one of the vials within the cartridge 170.

Although not specifically shown in FIG. 4, the synthesizer 100 may havemultiple sets of valves. The plurality of valves within the multiplesets of valves may be configured in a variety of ways to dispense thereagent solutions to a select one or more of the vials. For example, inone configuration, where each set of valves is identically configured,the synthesizer 100 is capable of simultaneously dispensing the samereagent solution in parallel from multiple sets of valves tocorresponding banks of vials. In this configuration, the multiple banksof vials may be processed in parallel. In the alternative, eachindividual valve within multiple sets of valves may contain entirelydifferent reagent solutions such that there is no duplication of reagentsolutions among any individual valves in the multiple sets of valves.This configuration allows the synthesizer 100 to build polymer chainsrequiring a large variety of reagent solutions without changing thereagent solutions associated with each valve.

The motor 445 is preferably mounted to the base 105 through the gear box440 and the motor connector 465. The chamber bowl 400 preferablysurrounds the motor connector 465 and remains stationary relative to thebase 105. The chamber bowl 400 is designed to hold any reagent solutionspilled from the plurality of vials 160 during the purging process.Further, the chamber bowl 400 is configured with a tall shoulder toinsure that spills are contained within the bowl 400. The chamber lipseal 450 preferably provides a seal around the motor connector 465 inorder to prevent the contents of the chamber bowl 400 from flowing intothe gear box 440. The chamber seal 450 is preferably composed of aflexible and resilient material such as Teflon® or elastomer whichconforms to any irregularities of the motor connector 465.Alternatively, the chamber seal can be composed of any other appropriatematerial. Additionally, the chamber seal 450 has frictionless propertieswhich allow the motor connector 465 to rotate freely within the seal.For example, coating this flexible material with Teflon® helps toachieve a low coefficient of friction.

The drain plate 410 is coupled to the motor connector 465. The cartridge170 is coupled to the drain plate 410. More specifically, the drainplate 410 is attached to the motor connector 465 which rotates the drainplate 410 while the motor 445 is operating and the gear box 440 isturning. The cartridge 170 and the drain plate 410 are preferablyconfigured to rotate as a single unit. The drain plate 410 is configuredto catch and direct the reagent solutions as the reagent solutions areexpelled from the plurality of vials. While operating, the motor 445 isconfigured to rotate both the cartridge 170 and the drain plate 410through the gear box 440 and the motor connector 465. The chamber seal450 allows the motor connector 465 to rotate the cartridge 170 and thedrain plate 410 through a portion of the chamber bowl 400 while stillcontaining any reagent solutions in the chamber bowl 400.

The controller 480 is coupled to the motor 445 to activate anddeactivate the motor 445 in order to rotate the cartridge 170 and thedrain plate 410. The controller 480 provides embedded control to thesynthesizer and controls not only the operation of the motor 445, butalso the operation of the valves 470 and the waste tube system 430.

FIG. 5 illustrates a detailed top view of the drain plate 410. The drainplate 410 has a plurality of securing holes 780 for attaching to themotor connector 465. The drain plate 410 also has a top surface 715which attaches to the underside of the cartridge 170. As statedpreviously, the cartridge 170 holds the plurality of vials grouped intothe plurality of banks.

The drain plate 410 preferably has four collection areas 705, 710, 720and 730, to correspond to the four banks within the cartridge 170. Eachof these four collection areas 705, 710, 720 and 730 forms a recessedarea below the top surface 715 and is designed to contain and directmaterial flushed from the vials within the bank above the collectionarea. Each of the four collection areas 705, 710, 720 and 730 ispositioned below a corresponding one of the banks of vials on thecartridge 170. The drain plate 410 is rotated with the cartridge 170 tokeep the corresponding collection area below the corresponding bank.

There are four drains 740, 750, 760 and 770, each of which is locatedwithin one of the four collection areas 705, 710, 720 and 730,respectively. In use, the collection areas 705, 710, 720 and 730 areconfigured to contain material flushed from corresponding vials and passthat material through the drains 740, 750, 760 and 770, respectively.Preferably, there is a collection area and a drain corresponding to eachbank of vials within the cartridge 170. Alternatively, any appropriatenumber of collection areas and drains can be included within a drainplate.

The clear window 460 (FIG. 4) is attached to a top plate of the base 105and covers the area above the cartridge 170. The top plate of the base105 opens up allowing an operator or maintenance person access to theinterior of the synthesizer 100. The clear window 460 allows theoperator to observe the synthesizer 100 in operation while providing apressure sealed environment within the interior of the synthesizer 100.As shown in FIG. 4, there are a plurality of through holes 520 in theclear window 460 to allow the plurality of dispense lines 140 to extendthrough the clear plate 460 to dispense material into the vials.

The clear window 460 also includes a gas fitting 530 attachedtherethrough. The gas fitting 530 is coupled to a gas line 540. The gasline 540 preferably continuously emits a stream of inert gas which flowsinto the synthesizer 100 through the gas fitting 530 and flushes outtraces of air and water from the plurality of vials 160 within thesynthesizer 100. Providing the inert gas flow through the gas fitting530 into the synthesizer 100 prevents the polymer chains being formedwithin the vials from being contaminated without requiring the pluralityof vials 160 to be hermetically sealed and isolated from the outsideenvironment.

The drain 740 is attached to the drain plate 410 and is positioned tocorrespond with a bank of vials held within the cartridge 170. The drain740 corresponds to a single bank of vials and is primarily utilized forflushing material from this single bank of vials. As described above,preferably, each bank of vials has a corresponding drain.

The waste tube system 430 is preferably utilized to provide apressurized environment for flushing material including reagentsolutions from the plurality of vials located within a correspondingbank of vials and expelling this material from the synthesizer 100.Alternatively, the waste tube system 430 can be used to provide a vacuumfor drawing material from the plurality of vials located within acorresponding bank of vials.

An isolated cross-sectional view of the waste tube system 430 isillustrated in FIG. 7. The waste tube system 430 comprises a stationarytube 490 and a mobile waste tube 500. The stationary tube 490 and themobile waste tube 500 are slidably coupled together. The stationary tube490 is attached to the chamber bowl 410 and does not move relative tothe chamber bowl 400. In contrast, the mobile tube 500 is capable ofsliding relative to the stationary tube 490 and the chamber bowl 400.When in an inactive state, the waste tube system 430 does not expel anyreagent solutions. During the inactive state, both the stationary tube490 and the mobile tube 500 are preferably mounted flush with the bottomportion of the chamber bowl 400.

When in an active state, the waste tube system 430 purges the materialfrom the corresponding bank of vials. During the active state, themobile tube 500 rises above the bottom portion of the chamber bowl 400towards the drain plate 410. The drain plate 410 is rotated over toposition a drain corresponding to the bank to be flushed, above thewaste tube system 430. The mobile tube 500 then couples to this drainand the material is flushed out of the corresponding bank of vials andinto the drain plate 420. The reagent solution is purged from thecorresponding bank of vials due to a sufficient pressure differentialbetween a top opening 610 (FIG. 6) and a bottom opening 640 (FIG. 6) ofeach vial. This sufficient pressure differential is preferably createdby coupling the mobile waste tube 500 to the corresponding drain.Alternatively, the waste tube system 430 may also include a vacuumdevice 510 coupled to the stationary tube 490 wherein the vacuum device510 is configured to provide this sufficient pressure differential toexpel material from the corresponding bank of vials. When thissufficient pressure differential is generated, the excess materialwithin the vials being flushed, then flows through the correspondingdrain and is carried away via the waste tube system 430.

When engaging the corresponding drain to flush a bank of vials,preferably the mobile tube 500 slides over the corresponding drain suchthat the mobile tube 500 and the drain act as a single unit.Alternatively, as illustrated in FIG. 9 the waste tube system 530includes a mobile tube 520 which engages the corresponding drain bypositioning itself directly below the drain and then sealing against thedrain without sliding over the drain. The mobile tube 520 includes adrain seal 540 positioned on top of the mobile tube 520. In thisembodiment, during a flushing operation, the mobile tube 520 is notlocked to the corresponding drain. In the event that this drain isaccidentally rotated while the mobile waste tube 520 is engaged with thedrain, the drain and mobile tube 500 of the synthesizer 100 will simplydisengage and will not be damaged. If this occurs while material isbeing flushed from a bank of vials, any spillage from the drain iscontained within the chamber bowl 400.

Configuring the waste tube system 430 to expel the reagent solutionwhile the mobile waste tube 500 is coupled to the drain allows thepresent invention to selectively purge individual banks of vials.Instead of simultaneously purging all the vials within the synthesizer100, the present invention selectively purges individual banks of vialssuch that only the vials within a selected bank or banks are purged.

Preferably, the synthesizer 100 includes two waste tube systems 430 forflushing two banks of vials simultaneously. Alternatively, anyappropriate number of waste tube systems can be included within thesynthesizer 100 for selectively flushing banks of vials.

FIG. 6 illustrates a cross sectional view of a vial 181. The vial 181 isan integral portion of the synthesizer 100. Generally, the polymer chainis formed within the vial 181. More specifically, the vial 181 holds aCPG 650 on which the polymer chain is grown. As stated previously, tocreate the polymer chain, the CPG 650 is sequentially submerged invarious reagent solutions for a predetermined amount of time. With eachdeposit of a reagent solution, an additional unit is added to theresulting polymer chain. Preferably, the CPG 650 is held within the vial181 by a frit 620. The vial 181 includes a top opening 610 and a bottomopening 640. During the dispensing process, the vial 181 is filled witha reagent solution through the top opening 610. Then, during the purgingprocess, the vial 181 is drained of the reagent solution through thebottom opening 640. The frit 620 prevents the CPG 650 or other supportfrom being flushed away during the purging process. A precision boredinterior 630 holds the frit 620 in place and provides a consistentcompression and seal with the frit 620. As a result of the precisionbored interior 630, there is a consistent flow of the reagent solutionthrough each vial during both the dispensing and purging processes.

The exterior of each vial 181 also has a precise dimension around thesupport 660. This support 660 fits within the receiving hole 185 withinthe cartridge 170 and provides a pressure tight seal around each vialwithin the cartridge 170. Preferably, each vial 181 is formed ofpolyethylene by a molded process. Alternatively, the vials 181 can beformed using any appropriate process and any appropriate material.

In use, the controller 480 which is coupled to the motor 445, the valves470, and the waste tube system 430 coordinates the operation of thesynthesizer 100. The controller 480 controls the motor 445 such that thecartridge is rotated to align the correct vials with the dispense lines140 corresponding to the appropriate valves 470 during dispensingoperations and that the correct one of the drains 740, 750, 760 and 770,are aligned with an appropriate waste tube system 430 during a flushingoperation.

FIG. 8 illustrates a computer system 800 coupled to the synthesizer 100.The computer system 800 preferably provides the synthesizer 100 andspecifically the controller 480 with operating instructions. Theseoperating instructions include rotating the cartridge 170 to apredetermined position, dispensing one of a plurality of reagentsolutions into selected vials through the valves 470 and dispense lines140, flushing the first bank of vials 115 and/or the second bank ofvials 125, and coordinating a timing sequence of these synthesizerfunctions. Preferably, the computer system 800 allows the user to inputdata representing reagent solution sequences to form a polymer chain,oligonucleotides, and other organic compounds via a graphical userinterface. After the user inputs this data, the computer system 800instructs the synthesizer 100 to perform appropriate functions withoutany further input from the user. The computer system 800 preferablyincludes a processor 810, an input device 820 and a display 830. Thecomputer 800 can be configured as a laptop or a desktop.

The present invention forms custom defined sequences such asoligonucleotides, polymers and other organic compounds. The presentinvention has a plurality of vials divided among a plurality of bankswherein a custom sequence can be synthesized within each vial. Thepresent invention forms these custom sequences without constantsupervision by the user.

Each bank of vials has a drain and can be selectively purged. To performa purging operation, the drain of the corresponding bank of vials iscoupled to a mobile waste tube. After coupling the drain to the mobilewaste tube, a pressure differential is formed and the material withineach of the vials within the corresponding bank of vials is expelled.

The present invention preferably utilizes a plurality of valves dividedinto a plurality of banks of valves to perform a filling operation todispense reagent solutions to various vials during the fillingoperation. Each of the plurality of valves can be configured to dispensedifferent reagent solutions to form complex custom sequences. In aparallel configuration, the plurality of valves can be configured todispense the same reagent solution simultaneously to more than one vial.

The present invention allows the user to enter the custom sequence intoa computer system. This computer system controls the fill operation andthe purge operation such that appropriate vials are filled with thecorrect reagent solutions and the appropriate banks of vials are purgedat the appropriate times within the sequence. Further, the computersystem ensures that the correct quantity of reagent solution isdeposited and that the reagent solution remains in the appropriate vialfor the correct amount of time.

Each vial of the present invention has a precision bored interior thatis configured to produce a consistent seal with a frit. By having theconsistent seal with the frit, the reagent solutions flow evenly andpredictably through each vial of the present invention. Each vial alsoincludes a precise exterior dimension to consistently fit within thecartridge and provide a pressure tight seal around the vial within thecartridge.

In operation, when building sequence defined oligonucleotides, polymerchains or other organic compounds, the synthesizer 100 rotates theappropriate vials under the dispense tubes corresponding to theappropriate valves 470 at the appropriate times to build the desiredsequence or compound. The synthesizer also rotates the banks of vialsover a corresponding waste tube system 430 in order to flush materialfrom the vials, as appropriate. As discussed above, the banks of vialsheld within a cartridge can be selectively purged to allow a user topotentially build different sequences or compounds within each vial. Inthis manner, one bank of vials can be purged, while another bank ofvials is in a wait period. While purging one bank of vials, a dispenseoperation could also be performed on vials other than the bank or banksof vials being purged, if the position of the vials corresponds to theappropriate valves. However, during a purging operation, the cartridge170 cannot be rotated or the drain 740 will disengage from the mobilewaste tube 500.

To perform a dispense operation for a selected vial, the motor 445rotates the cartridge 170 in response to the computer system 800 suchthat the vial 181 is positioned below the appropriate dispense line 140corresponding to the valve 470. Once the vial 181 is properly positionedbelow this dispense line 140, the valve is opened by the controller 480and the solution controlled by the valve 470 flows through the dispensetube 140 into the vial 181. The valve 470 is then closed after apredetermined period of time corresponding to the precise amount ofsolution to be dispensed into the vial 181.

To purge material from a bank of vials, the motor 445 rotates thecartridge 170 in response to the computer system 800 such that the draincorresponding to the bank of vials to be purged is positioned above thewaste tube system 430. The mobile waste tube 500 is then raised toengage the drain and the material within the bank of vials is expelledfrom the vials through the waste tube system 430.

The present invention has been described in terms of specificembodiments incorporating details to facilitate the understanding of theprinciples of construction and operation of the invention. Suchreference herein to specific embodiments and details thereof is notintended to limit the scope of the claims appended hereto.

It will be apparent to those skilled in the art that modifications maybe made in the embodiment chosen for illustration without departing fromthe spirit and scope of the invention. Specifically, it will be apparentto one of ordinary skill in the art that the device of the presentinvention could be implemented in several different ways and theembodiments disclosed above are only exemplary of the preferredembodiment and the alternate embodiments of the invention and is in noway a limitation.

We claim:
 1. A cartridge comprising: a. a plurality of receiving holes; b. a plurality of individually removable vials configured to fit within a corresponding one of the receiving holes, each of the vials comprising a protruding support and a bored interior having a consistent dimension configured to hold a frit for retaining material within the vial above the frit and maintain a consistent flow through the bored interior during a flushing procedure by only forming a pressure differential to expel material from the vial; wherein the bored interior linearly tapers from the protruding support to the frit.
 2. The cartridge according to claim 1 wherein each vial further comprises an exterior dimension configured to fit within the corresponding one of the receiving holes, thereby providing a pressure-tight seal between the vial and the cartridge.
 3. The cartridge according to claim 1, wherein each vial further comprises a frit held within the bored interior.
 4. The cartridge according to claim 3, wherein each vial further comprises a solid support retained within the vial above the frit after the flushing procedure.
 5. The cartridge according to claim 4, wherein the solid support is controlled pore glass beads.
 6. The cartridge according to claim 1, wherein the material is a reagent solution dispensed into the bored interior.
 7. A cartridge for holding one or more vials, the cartridge comprising: a. one or more receiving holes; and b. one or more vials, each vial comprising an exterior dimension to fit directly within a corresponding receiving hole thereby providing a pressure-tight seal directly between the vial and the cartridge, a bored interior having a consistent dimension to maintain a consistent flow through the bored interior during flushing procedures by only forming a pressure differential to expel material from the vial and a solid support retained within the vial above a frit after flushing procedures; wherein the bored interior linearly tapers from the exterior dimension to the frit.
 8. The cartridge according to claim 7, further comprising a frit held within the bored interior.
 9. The cartridge according to claim 7, wherein the solid support is controlled pore glass beads.
 10. A cartridge for holding one or more vials, the cartridge comprising: a. one or more receiving holes; and b. one or more vials, each vial comprising: i. a bored interior having a consistent dimension to hold a frit for retaining material above the frit and maintain a consistent flow through the bored interior during a flushing procedure by only forming a pressure differential to expel material from the vial; ii. a top opening through which material is dispensed into the bored interior; iii. a bottom opening of a diameter to retain material within the bored interior when no pressure differential is applied and through which material is flushed during the flushing procedure; and iv. an exterior dimension to fit directly within a receiving hold of a cartridge to form a pressure-tight seal directly between the vial and the cartridge when the vial is inserted into a receiving hole of the cartridge; wherein the bored interior linearly tapers from the exterior dimension to the frit.
 11. The cartridge according to claim 10, wherein each vial further comprises a frit held within the bored interior.
 12. The cartridge according to claim 11, wherein each vial further comprises a solid support retained within the vial above the frit after the flushing procedure.
 13. The cartridge according to claim 12, wherein the solid support is controlled pore glass beads.
 14. The cartridge according to claim 10, wherein the material dispensed into the bored interior is a reagent solution.
 15. A cartridge for holding one or more vials, the cartridge comprising: a. one or more receiving holes; and b. one or more vials, each vial comprising: i. a bored interior having a consistent dimension to hold a frit for retaining material above the frit and maintain a consistent flow through the bored interior during a flushing procedure by only forming a pressure differential to expel material from the vial, wherein the consistent dimension is consistent for each of the plurality of vials; ii. a top opening through which material is dispensed into the bored interior; iii. a bottom opening of a diameter to retain material within the bored interior when no pressure differential is applied and through which material is flushed during the flushing procedure; iv. an exterior dimension configured to fit directly within a the receiving holes to form a pressure-tight seal directly between the vial and the cartridge when the vial is inserted into a receiving hole of the cartridge, wherein the exterior dimension is consistent for each of the plurality of vials such that any of the vials will consistently fit within the receiving hole of the cartridge; and v. a solid support retained within the vial above the frit after the flushing procedure; wherein the bored interior linearly tapers from the exterior dimension to the frit.
 16. The cartridge according to claim 15, wherein each vial further comprises a frit held within the bored interior.
 17. The cartridge according to claim 15, wherein the solid support is controlled pore glass beads.
 18. The cartridge according to claim 15, wherein the material is a reagent solution dispensed into the bored interior.
 19. A cartridge for holding one or more vials, the cartridge comprising: a. one or more receiving holes; and b. one or more vials, each vial comprising: i. a frit; ii. a solid support; iii. a bored interior having a consistent dimension to hold the frit for retaining the solid support above the frit and maintain a consistent flow through the bored interior during a flushing procedure by only forming a pressure differential to expel material from the vial, wherein the solid support and material formed on the solid support is retained above the frit, within the vial, during a flushing procedure; iv. a top opening through which material is dispensed into the bored interior; v. a bottom opening of a diameter to retain material within the bored interior when no pressure differential is applied and through which material is flushed during the flushing procedure; and vi. a protruding support that extends along the entire circumference of the top opening and is configured to form a pressure-tight seal directly between the vial and the cartridge when the vial is inserted into the one or more receiving holes of the cartridge; wherein the bored interior linearly tapers from the exterior support to the frit.
 20. The cartridge according to claim 19, wherein the solid support is controlled pore glass beads.
 21. The cartridge according to claim 19, wherein the material is a reagent solution dispensed into the bored interior. 